The principal aim of this study is to investigate the cardiac uptake of 89Zr-GSK2398852 in subjects with transthyretin cardiomyopathy amyloidosis (ATTR-CM), and its biodistribution to other organs. Low doses of GSK2398852 will be co-administered at levels not high enough for therapeutic benefit. This study will be conducted in two parts: Part A and Part B. Subjects in Part A will participate in up to two dosing sessions and subjects in Part B will participate in one dosing session. Subjects will undergo up to 3 PET scans at varying intervals after 89Zr-GSK2398852 administration. The total duration of study will be approximately 3 to 4 months for subjects in Part A and approximately 2 months for subjects in Part B. Part B of the study will be triggered based on data obtained in Part A and other emerging data.
Name: GSK2315698 (CPHPC)
Description: GSK2315698 will be administered as 20 milligrams per hour (20 mg/hour) IV infusion (in the vein) for up to 72 hours followed by 60 milligrams (mg) three times daily as SC injection for 8 days. Dose level and frequency will be adjusted according to renal function.Type: DrugSubjects with ATTR-CM in Part A Subjects with ATTR-CM in Part B
Name: GSK2398852 (unlabeled anti-SAP mAb)
Description: Subjects will be administered up to 490 mg of GSK2398852, IV. Dose level will be adjusted based on emerging imaging data.Type: DrugSubjects with ATTR-CM in Part A Subjects with ATTR-CM in Part B
Name: 89Zr-GSK2398852 (89Zr-labeled anti-SAP mAb)
Description: 89Zr-GSK2398852 will be available as solution containing 10 mg 89Zr-GSK2398852 for Infusion. Subjects will be administered 37 (Megabecquerel) MBq radioactive dose of 89Zr-GSK2398852 by the IV route at each dosing session.Type: DrugSubjects with ATTR-CM in Part A Subjects with ATTR-CM in Part B
Description: PET images will be visually reviewed to assess the radioactivity distribution. SUV is the measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight.
Measure: Standardized Uptake Values (SUV) in focal anatomical regions of the heart following 80-200 milligrams (mg) dose of anti-SAP mAb Time: Up to Day 6Description: PET images will be visually reviewed to assess the radioactivity distribution. SUV is the measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight.
Measure: SUV in focal anatomical regions of the heart following an anti-SAP mAb dose between 200 mg and <=500 mg Time: Up to Day 6Description: PET images will be visually reviewed to assess the radioactivity distribution. SUV is the measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight.
Measure: SUV of whole heart following 80-200 mg dose of anti-SAP mAb Time: Up to Day 6Description: PET images will be visually reviewed to assess the radioactivity distribution. SUV is the measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight.
Measure: SUV of whole heart following an anti-SAP mAb dose between 200 mg and <=500 mg Time: Up to Day 6Description: PET images will be visually reviewed to assess the radioactivity distribution. SUV is the measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight. Focal radioactivity uptake in different tissues will be evaluated.
Measure: Focal radioactivity uptake after 80-200 mg dose of anti-SAP mAb Time: Up to Day 6Description: PET images will be visually reviewed to assess the radioactivity distribution. SUV is the measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight. Focal radioactivity uptake in different tissues will be evaluated.
Measure: Focal radioactivity uptake after an anti-SAP mAb dose between 200 mg and <=500 mg Time: Up to Day 6Description: PET images will be visually reviewed to assess the radioactivity distribution. SUV is the measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight. Total radioactivity uptake in different tissues will be evaluated.
Measure: Total radioactivity uptake after 80-200 mg dose of anti-SAP mAb Time: Up to Day 6Description: PET images will be visually reviewed to assess the radioactivity distribution. SUV is the measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight. Total radioactivity uptake in different tissues will be evaluated.
Measure: Total radioactivity uptake after an anti-SAP mAb dose between 200 mg and <=500 mg Time: Up to Day 6Description: Blood samples will be collected at indicated time points for measurement of plasma concentrations of GSK2398852. Plasma concentrations of GSK2398852, will be the total of both 89Zr-labeled and unlabeled mAb.
Measure: Maximum concentration in plasma (Cmax) of total mAb Time: Day 3 (pre-dose, 4 hours, 7 hours post-dose), Day 4, Day 5, Day 6 and Day 7 post-doseDescription: Blood samples will be collected at indicated time points for measurement of plasma concentrations of GSK2398852. Plasma concentrations of GSK2398852, will be the total of both 89Zr-labeled and unlabeled mAb.
Measure: Time associated with Cmax (Tmax) of total mAb Time: Day 3 (pre-dose, 4 hours, 7 hours post-dose), Day 4, Day 5, Day 6 and Day 7 post-doseDescription: Blood samples will be collected at indicated time points for measurement of plasma concentrations of GSK2398852. Plasma concentrations of GSK2398852, will be the total of both 89Zr-labeled and unlabeled mAb.
Measure: Clearance of total mAb Time: Day 3 (pre-dose, 4 hours, 7 hours post-dose), Day 4, Day 5, Day 6 and Day 7 post-doseDescription: Blood samples will be collected at indicated time points for measurement of plasma concentrations of GSK2398852. Plasma concentrations of GSK2398852, will be the total of both 89Zr-labeled and unlabeled mAb.
Measure: Terminal half-life (T1/2) of total mAb Time: Day 3 (pre-dose, 4 hours, 7 hours post-dose), Day 4, Day 5, Day 6 and Day 7 post-doseDescription: Blood samples will be collected at indicated time points for measurement of plasma concentrations of GSK2398852. Plasma concentrations of GSK2398852, will be the total of both 89Zr-labeled and unlabeled mAb.
Measure: Area under the concentration-time profile (AUC) of total mAb Time: Day 3 (pre-dose, 4 hours, 7 hours post-dose), Day 4, Day 5, Day 6 and Day 7 post-doseDescription: Blood samples will be collected at indicated time points for measurement of radioactivity. The radioactivity will reflect the total concentration of 89Zr-GSK2398852 and its radioactive metabolites. Plasma radioactive concentration will be measured by scintillation counter.
Measure: Cmax of 89Zr- GSK2398852 pharmacokinetics of radioactivity (radio-PK) Time: Day 3 (10 minutes, 60 minutes, 4 hours, 7 hours post-dose), Day 4, Day 5 and Day 6 post-doseDescription: Blood samples will be collected at indicated time points for measurement of radioactivity. The radioactivity will reflect the total concentration of 89Zr-GSK2398852 and its radioactive metabolites. Plasma radioactive concentration will be measured by scintillation counter.
Measure: Tmax of 89Zr- GSK2398852 radio-PK Time: Day 3 (10 minutes, 60 minutes, 4 hours, 7 hours post-dose), Day 4, Day 5 and Day 6 post-doseDescription: Blood samples will be collected at indicated time points for measurement of radioactivity. The radioactivity will reflect the total concentration of 89Zr-GSK2398852 and its radioactive metabolites. Plasma radioactive concentration will be measured by scintillation counter.
Measure: T1/2 of 89Zr- GSK2398852 radio-PK Time: Day 3 (10 minutes, 60 minutes, 4 hours, 7 hours post-dose), Day 4, Day 5 and Day 6 post-doseDescription: Blood samples will be collected at indicated time points for measurement of radioactivity. The radioactivity will reflect the total concentration of 89Zr-GSK2398852 and its radioactive metabolites. Plasma radioactive concentration will be measured by scintillation counter.
Measure: AUC of 89Zr- GSK2398852 radio-PK Time: Day 3 (10 minutes, 60 minutes, 4 hours, 7 hours post-dose), Day 4, Day 5 and Day 6 post-doseDescription: An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; other important medical events which may require medical or surgical intervention.
Measure: Number of subjects with adverse events (AEs) and serious adverse events (SAEs) Time: Up to Day 28Description: Rash will be graded as Grade 1 to Grade 4 based on symptoms and body surface area affected.
Measure: Number of subjects with skin rashes Time: Up to Day 28Description: Cardiovascular adverse events will include myocardial infarction/unstable angina, congestive heart failure, arrhythmias, valvulopathy, pulmonary hypertension, cerebrovascular events/stroke and transient ischemic attack, peripheral arterial thromboembolism, deep venous thrombosis/pulmonary embolism and revascularization.
Measure: Number of subjects with cardiac adverse events Time: Up to Day 28Description: Number of subjects with infusion related reactions will be summarized.
Measure: Number of subjects with infusion related reactions Time: Up to Day 28Description: The following hematology parameters will be assessed: platelet count, red blood cell (RBC) count, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), percentage of reticulocytes, neutrophils, lymphocytes, monocytes, eosinophils and basophils.
Measure: Number of subjects with abnormal hematology parameters Time: Up to Day 28Description: The following clinical chemistry parameters will be evaluated: blood urea nitrogen (BUN), creatinine, glucose (non-fasting), potassium, sodium, calcium, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total and direct bilirubin, total protein and albumin.
Measure: Number of subjects with abnormal clinical chemistry parameters Time: Up to Day 28Description: The following parameters will be evaluated: specific gravity, potential hydrogen (pH), glucose, protein, blood and ketones by dipstick method. Urine microscopy will be performed if indicated.
Measure: Number of subjects with abnormal urine parameters Time: Up to Day 28Description: The following cardiac chemistry parameters will be evaluated: troponin T and N-terminal prohormone of brain natriuretic peptide (NT-ProBNP).
Measure: Number of subjects with cardiac safety parameters of clinical significance Time: Up to Day 28Description: 12-lead ECGs will be obtained in a semi-supine position using an automated ECG machine after approximately 5 minutes of rest for the subject.
Measure: Number of subjects with abnormal electrocardiogram (ECG) Time: Up to Day 28Description: Inpatient cardiac monitoring will be performed using inpatient lead II cardiac telemetry.
Measure: Number of subjects with abnormal inpatient cardiac telemetry Time: Up to Day 11Description: Outpatient cardiac monitoring will be performed using a non-implantable remote cardiac telemetry device.
Measure: Number of subjects with abnormal outpatient cardiac telemetry Time: Up to Day 18Description: Temperature will be measured in a semi-supine position after 5 minutes of rest.
Measure: Number of subjects with abnormal temperature Time: Up to Day 28Description: Systolic and diastolic blood pressure will be measured in a semi-supine position after 5 minutes of rest.
Measure: Number of subjects with abnormal blood pressure Time: Up to Day 28Description: Pulse rate will be measured in a semi-supine position after 5 minutes of rest.
Measure: Number of subjects with abnormal pulse rate Time: Up to Day 28Description: Respiratory rate will be measured in a semi-supine position after 5 minutes of rest.
Measure: Number of subjects with abnormal respiratory rate Time: Up to Day 28Description: A brief physical examination will be performed, including assessments of the skin, lungs, cardiovascular system and abdomen (liver and spleen).
Measure: Number of subjects with abnormal physical examination findings Time: Up to Day 11Allocation: Non-Randomized
Sequential Assignment
There is one SNP
b) Hereditary ATTR amyloidosis (example, TTR Val30Met) should have a known amyloidogenic TTR mutation demonstrated by genotyping and is recognized to be primarily associated with cardiomyopathy and one of the following: i) Definite histochemical identification of amyloid by Congo red staining and green birefringence in crossed polarized light in cardiac or other tissue biopsy and identification of TTR as the amyloid fibril protein either by immunohistochemistry or proteomic analysis. --- Val30Met ---